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RESEARCH PRODUCT
Immunoproteasome LMP2 60HH Variant Alters MBP Epitope Generation and Reduces the Risk to Develop Multiple Sclerosis in Italian Female Population
Daniela GalimbertiFederica EspositoBenedetta NacmiasMichele MishtoMichele MishtoClaudio FranceschiSandra D'alfonsoElio ScarpiniElena CelliniUlrike SeifertC. LigorioPeter M. KloetzelMaurizio LeoneMara GiordanoFilippo Martinelli-boneschiAurelia SantoroMaria Pia AmatoFlorinda ListìChiara FenoglioCalogero CarusoElena BellavistaKathrin Textoris-taubeLuigi M.e. GrimaldiMaria Pia Foschinisubject
MaleT cells proteasomes multiple sclerosis parietal lobeMuscle ProteinsImmunoproteasomeEpitopeEpitopesGene FrequencyRisk FactorsCytotoxic T cellFunding: This work was financed in part by the grant Giovani Ricercatori 2007 from Italian Ministry of Health to MM DG and FMB by a grant from the European Commission Integrated Project PROTEOMAGE (FP6) to CF by the finalized projects of Fondazione Italiana Sclerosi Multipla (FISM) cod. 2003/R26 and BioPharmaNet to CF and 2002/R/40 and 2005/R/10 2008/R/11 (Genoa) to SD'A by the University of Bologna (FRO) to MPF by the Regione Piemonte (Ricerca Sanitaria Finalizzata Project and Ricerca Sanitaria Applicata-CIPE Project) to SD'A by Associazione Amici del Centro Dino Ferrari and IRCCS Ospedale Maggiore Policlinico Milano to DG and by the grants Sonderforschungsbereich (SFB-507 SFB-421) to PMK and US the grants TR43 and Neurocure to PMK. MM benefited from the A.V. Humboldt PostDoc fellowship. The funders had no role in study design data collection and analysis decision to publish or preparation of the manuscript.MultidisciplinaryMicrogliaQRBrainMiddle AgedImmunohistochemistryCysteine EndopeptidasesOligodendrogliamedicine.anatomical_structureItalyImmunoproteasome; multiple sclerosis; italian populationmultiple sclerosiImmunology/Antigen Processing and RecognitionMedicineFemaleMicrogliaNeuroscience/Neurobiology of Disease and RegenerationResearch ArticleProtein BindingAdultProteasome Endopeptidase ComplexMultiple SclerosisGenotypeScienceMolecular Sequence DataImmunology/AutoimmunityBiologySex FactorsMHC class IHLA-A2 AntigenmedicineHumansAmino Acid SequenceAlleleHLA-A AntigensMultiple sclerosisMacrophagesMyelin Basic Proteinmedicine.diseaseMyelin basic proteinImmunologybiology.proteinitalian populationCD8description
BackgroundAlbeit several studies pointed out the pivotal role that CD4+T cells have in Multiple Sclerosis, the CD8+ T cells involvement in the pathology is still in its early phases of investigation. Proteasome degradation is the key step in the production of MHC class I-restricted epitopes and therefore its activity could be an important element in the activation and regulation of autoreactive CD8+ T cells in Multiple Sclerosis.Methodology/principal findingsImmunoproteasomes and PA28-alphabeta regulator are present in MS affected brain area and accumulated in plaques. They are expressed in cell types supposed to be involved in MS development such as neurons, endothelial cells, oligodendrocytes, macrophages/macroglia and lymphocytes. Furthermore, in a genetic study on 1262 Italian MS cases and 845 controls we observed that HLA-A*02+ female subjects carrying the immunoproteasome LMP2 codon 60HH variant have a reduced risk to develop MS. Accordingly, immunoproteasomes carrying the LMP2 60H allele produce in vitro a lower amount of the HLA-A*0201 restricted immunodominant epitope MBP(111-119).Conclusion/significanceThe immunoproteasome LMP2 60HH variant reduces the risk to develop MS amongst Italian HLA-A*02+ females. We propose that such an effect is mediated by the altered proteasome-dependent production of a specific MBP epitope presented on the MHC class I. Our observations thereby support the hypothesis of an involvement of immunoproteasome in the MS pathogenesis.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2010-02-01 | PLoS ONE |